Dissolution studies

Putt, M. S. Kleber, C. J. (1985). Dissolution studies of human enamel treated with aluminium solutions. Journal of Dental Research, 64, 437-40. 

K Arnold, N Gerber, G Levy. Absorption and dissolution studies on sodium diphenylhydantoin capsules. Can J Pharm Sci 5(4) 89-92, 1970. 

Detailed development pharmaceutics data where relevant studies have been undertaken— e.g., in vitro dissolution studies. 

The information requirements for products such as prolonged-release oral dosage forms will depend on whether or not it has been possible, during the development of the product, to establish an in vivo-in vitro correlation between clinical data and dissolution studies. In vivo-in vitro correlations should be attempted using product at different stages of development, but bioavailability and pharmacokinetics data from pivotal clinical studies using at least pilot-scale production materials and possibly routine production material are particularly important. Where it is not possible to establish an in vivo-in vitro correlation, additional data will be required to compare the bioavailability of product developed at laboratory scale, pilot scale, and production scale. In the absence of an in vivo-in vitro correlation, the dissolution test will be a quality control tool rather than a surrogate marker for in vivo performance of the product. 

Product bioavailability is mentioned, especially where it is low. Where there are differences between the formulations tested for bioavailability during the development process and the formulation to be marketed, there is considerable discussion of the data provided on the bioequivalence of the different products and/or formulations. This is particularly so where, for example, early clinical studies were undertaken with capsules but the marketed dosage form is to be a tablet. Bioequivalence data and pharmacokinetic data (e.g., in crossover studies) and comparative dissolution studies are usually reported. This is particularly significant where the different strengths of the final products are not achieved by using different quantities of the same granulate formulation. Process optimization may also be addressed in such cases. 

In many diffusion problems of practical importance in the pharmaceutical sciences, such as intrinsic dissolution studies and drug release from solid dosage forms, the medium under consideration is not at rest. In addition to concentration changes due to diffusion, there are concentration changes by convection. External forces, such as pressure gradients and temperature differences, can cause convective flows. Although convection can also be caused by diffusion itself, our discussion is limited to convection caused by external forces, since convection produced by diffusion is negligible (less than 10%) for most pharmaceutical problems. 

Since dosage forms contain more than just active drug, it is of practical interest to understand how the various components from a multicomponent solid influence their own dissolution and release. Nelson [18] was one of the first pharma-ceuticists to ponder this question and perform the initial dissolution studies. Unfortunately, Nelson initially considered the dissolution of interacting solids (benzoic acid + trisodium phosphate), which is a more complicated and more complex situation than simple multicomponent dissolution of noninteracting solids. Nelson did show that for his benzoic acid and trisodium phosphate pellets, there was a maximum increase in benzoic acid dissolution in water at a mole fraction ratio of 2 1 (benzoic acid trisodium phosphate) and that the benzoic acid dissolution rate associated with the maximum rate was some 40 times greater than that of benzoic acid alone. 

Bonlokke, L., Christensen, F. N., Knutson, L., Kristensen, H. G., Lennernas, H., A new approach for direct in vivo dissolution studies of poorly soluble drugs, Pharm. Res. 

E. S. Kostewicz, U. Brauns, R. Becker, J. B. Dressman. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm. Res. 2002, 19, 345-349. 

It should be noted however that it is almost impossible to predict fully the in vivo dissolution rate due to the many factors involved, of which several have not yet been completely characterized. The introduction of new study techniques to directly follow drug dissolution in vivo in the human intestine should therefore be of importance [30, 31]. For example, in vivo dissolution studies discriminated between the dissolution rates of the two different particle sizes of spironolactone, based on the intestinal perfusate samples. In addition, dissolution rates of carba-mazepine obtained in vitro were significantly slower than the direct in vivo measurements obtained using the perfusion method. The higher in vivo dissolution rate was probably due to the efficient sink conditions provided by the high permeability of carbamazepine [30, 31]. 

In a bioanalytical method, analyses of blank samples (plasma, urine, or other matrix) should be obtained from at least six sources. Each blank sample should be tested for the possible interference of endogenous substances, metabolites, or degradation products. The response of the peaks interfering at the retention time of the analyte should be less than 20% of the response of a lower quantitation limit standard, and should be less than 5% of the response of the internal standard that was used [18, 19]. For dissolution studies, the dissolution media or excipients should not give a peak or spot that has an identical Rt or Rf value with the analyte [20]. 

The accuracy of a method should be assessed using a minimum of nine determinations conducted over a minimum range of three concentration levels (80%, 100%, and 120% of the target concentration) [37]. Experience from our laboratory has showed that by using at least five levels of concentrations in duplicate (i.e., 80%, 90%i, 100%i, 110%, and 120% of the target concentration), a better result can be achieved. For dissolution studies, the accuracy of the required profile should be tested at 40%, 75%, and 110% of the theoretical release) [20],... 

Sulfathiazole has been found to crystallize in three distinct polymorphic forms, all of which are kinetically stable in the solid state but two of which are unstable in contact with water [130]. As evident in Fig. 20, the initial intrinsic dissolution rates are different, but as forms I and II convert into form III, the dissolved concentrations converge. Only the dissolution rate of form III was constant during the studies, indicating it to be the thermodynamically stable form at room temperature. Aqueous suspensions of forms I or II were all found to convert into form III over time, supporting the finding of the dissolution studies. Interestingly, around the melting points of the three polymorphs, form I exhibited... 

Numerous laboratory dissolution studies have tested for the effects of many of the aforementioned surface characteristics. 

Dissolution is also used to identify bioavailability (BA) problems and to assess the need for further BE studies relative to scale-up and post-approval Changes (SUPAC), where it functions as a signal of bioinequivalence. In vitro dissolution studies for all product formulations investigated (including prototype formulations) are encouraged, particularly if in vivo absorption characteristics can be defined for the different product formulations. With such efforts, it may be possible to achieve an in vitro/in vivo correlation. When an in vitro correlation or association is available, the in vitro test can serve not only as a quality control (QC) specification for the manufacturing process, but also as an indicator of in vivo product performance. 

Recently, an approach mimicking the GI tract and feasible for pharmaceutical dissolution studies has been published [47], Coming from the area of nutritional research, this approach reflects some promising aspects, such as relevant luminal pH values, peristalsis, luminal bacterial colonization, and relevant fluid volumes. However, permeation is only reflected by diffusion through hollow fiber membranes and thus is not in the scope of this chapter. Nevertheless, it will be interesting to see whether it will be possible to expand such a perfect in vitro device toward a more realistic intestinal epithelium. 

Figure 10. Comparison of isotopic fractionations determined between Fe(II)aq and Fe carbonates relative to mole fraction of Fe from predictions based on spectroscopic data (Polyakov and Mineev 2000 Schauble et al. 2001), natural samples (Johnson et al. 2003), DIR (Johnson et al. 2004a), and abiotic formation of siderite under equilibrium conditions (Wiesli et al. 2004). Fe(II)aq exists as the hexaquo complex in the study of Wiesli et al. (2004) hexaquo Fe(II) is assumed for the other studies. Total cations normalized to unity, so that end-member siderite is plotted at Xpe = 1.0. Error bars shown reflect reported uncertainties analytical errors for data reported by Johnson et al. (2004a) and Wiesli et al. (2004) are smaller than the size of the symbol. Fractionations measured on bulk carbonate produced by DIR are interpreted to reflect kinetic isotope fractionations, whereas those estimated from partial dissolutions are interpreted to lie closer to those of equilibrium values because they reflect the outer layers of the crystals. Also shown are data for a Ca-bearing DIR experiment, where the bulk solid has a composition of q)proximately Cao.i5Feo.85C03, high-Ca and low-Ca refer to the range measured during partial dissolution studies (Johnson et al. 2004a). Adapted from Johnson et al. (2004a).

Particles also cause the scattering of light in a process sample. Filtering probes and cells are available, which can eliminate most particles and bubbles from the optical path and make reliable process measurements possible for difhcult sample matrices (see e.g. Section 4.7). If particle formation is inherent, like insoluble excipients in dissolution studies of tablets, an ATR UV probe may be considered. 

In a recent study, Mirza et al. have pointed out that despite the obvious advantages, fiber-based dissolution studies are not yet implemented in industry. They have validated a fiber-optic based dissolution test for linearity, precision, accuracy, specificity and robusmess, with excellent results. 

HPbCD) during granulation was found to depend on the presence of sufficient ethanol the results were related to those from a dissolution study [255],... 

Most dissolution studies concentrate on establishing the mechanism of dissolution. There are few studies in which different oxides have been compared to provide... 

Although 2-line ferrihydrite has been used for dissolution studies, 6-line ferrihydrite has, to date, not been investigated. Fischer (1976) compared the dissolution behaviour of three 2-line ferrihydrites in 0.2 M oxalate and found the slowest dissolution rate for a slowly precipitated sample and faster dissolution for rapidly precipitated samples (hydrolysed by fast addition of NH3 or by bacterial oxidation of Fe citrate). Adsorbed silicate reduced the dissolution rate in oxalate probably by blocking surface Fe sites (Schwertmann Thalmann, 1976). 

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